Rationale for a metabolic approach in diabetic coronary patients

The incidence of ischaemic heart disease and acute myocardial infarction are greater in people with diabetes than in nondiabetic individuals. Heart disease patients with diabetes have a higher incidence of mortality during and following an acute myocardial infarction and a high risk for progression to heart failure post-infarction. The greater occurrence of ischaemic heart disease is partially due to a poorer coronary artery disease risk factor profile in diabetic patients, and, importantly, due to diabetes-induced abnormalities in the myocardium, termed 'diabetic cardiomyopathy'. The main metabolic abnormalities in the diabetic myocardium are impaired carbohydrate metabolism, specifically reduced pyruvate oxidation in the mitochondria and a greater reliance on fatty acids and ketone bodies as fuels. The healthy heart takes up glucose and lactate and converts them to pyruvate; however, in the diabetic heart there is a reduced capacity to oxidize pyruvate, and thus less glucose and lactate uptake. The defective metabolism is due to high circulating free fatty acids and ketone body concentrations in the plasma, resulting in greater acetyl-Co-enzyme A/Co-enzyme A and reduced nicotinamide adenonine dinucleotide/nicotinamide adenonine dinucleotide+ ratios in the mitochondria, and the subsequent inhibition of pyruvate dehydrogenase. Pharmacological inhibition of fatty acid oxidation during ischaemia increases myocardial pyruvate oxidation and provides clinical benefit to patients with stable angina or ischaemic left ventricular dysfunction. Recent clinical trials with trimetazidine, an inhibitor of the fatty acid beta-oxidation enzyme long chain 3-ketoacylthiolase, showed improvement in cardiac function and exercise performance in diabetic patients with ischaemic heart disease, illustrating the effectiveness of this approach in diabetes.